The brain monoamines, norepinephrine (NE), dopamine and serotonin have been strongly implicated in mediating aggression, mood, and affect. The major mode of disposition of these amines is by neuronal membrane uptake back into the nerve terminals, leaving a minor portion available for stimulation of post-synaptic receptors. Factors which may alter the proportion of released amines taken back up or made available for stimulation of receptors, should have profound effects on behavioral state. Until recently, the uptake process was considered a fixed property of nerve ending membranes, subject to alteration only by certain drugs. However, we have recently provided evidence that NE uptake is modulated behaviorally as well, e.g. by fighting or by electroconvulsive shock (ECS). These findings may explain the effectiveness of ECS in human depression. Using an in vitro preparation of brain synaptosomes to measure the kinetics of the uptake process, we propose to study in greater detail the nature of this behavioral modulation of neuronal membrane uptake, and to contrast it with drug-induced effects on uptake. We will study the effects of chronic administration of antidepressant drugs on sustained alteration in NE uptake affinity, contrasting the clinically effective agents that are also powerful inhibitors of NE uptake, desmethylimipramine and tranylcypromine, with nialamide which is a poor inhibitor of NE uptake, and relatively ineffective clinically. These studies should reveal the relative importance of inhibition of uptake in the therapy of human depression. More importantly, our studies should also shed light on the uptake mechanism itself, which is a common mode of action of a number of drugs that are popularly abused, e.g. cocaine and amphetamines.